Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients

Background:

The optimal treatment of desmoid tumours is controversial. We evaluated desmoid management in Dutch familial adenomatous polyposis (FAP) patients.

Methods:

Seventy-eight FAP patients with desmoids were identified from the Dutch Polyposis Registry. Data on desmoid morphology, management, and outcome were analysed retrospectively. Progression-free survival (PFS) rates and final outcome were compared for surgical vs non-surgical treatment, for intra-abdominal and extra-abdominal desmoids separately. Also, pharmacological treatment was evaluated for all desmoids.

Results:

Median follow-up was 8 years. For intra-abdominal desmoids (n=62), PFS rates at 10 years of follow-up were comparable after surgical and non-surgical treatment (33% and 49%, respectively, P=0.163). None of these desmoids could be removed entirely. Eventually, one fifth died from desmoid disease. Most extra-abdominal and abdominal wall desmoids were treated surgically with a PFS rate of 63% and no deaths from desmoid disease. Comparison between NSAID and anti-estrogen treatment showed comparable outcomes. Four of the 10 patients who received chemotherapy had stabilisation of tumour growth, all after doxorubicin combination therapy.

Conclusion:

For intra-abdominal desmoids, a conservative approach and surgery showed comparable outcomes. For extra-abdominal and abdominal wall desmoids, surgery seemed appropriate. Different pharmacological therapies showed comparable outcomes. If chemotherapy was given for progressively growing intra-abdominal desmoids, most favourable outcomes occurred after combinations including doxorubicin.     

Abdominal desmoid in familial adenomatous polyposis presenting as a pancreatic cystic lesion

A 17-year-old male with familial adenomatous polyposis (FAP) presented with chest pain and significant weight loss. An abdominal CT scan detected a cystic pancreatic lesion of unknown etiology. The patient therefore underwent surgical resection of the distal pancreas, which included the lesion, because of the known association of pancreatic cancer with FAP. Histopathological examination of the resected specimen showed a benign pancreatic cyst and fibrous plaque with desmoid fibromatosis adherent to the surface of the pancreas, serosa of the stomach, and colon. The fibrous plaque was histologically identical to the fibrous mesenteric plaque known to occur in FAP and associated mesenteric fibromatosis. We present pathologic evidence that the pancreatic cyst formation was induced by FAP-associated desmoid invasion. Desmoid growth should be considered in the differential diagnosis of a pancreatic cystic mass lesion in patients with FAP or its Gardner syndrome variant. This case report provides the first pathologic evidence for benign epithelial cyst formation in the pancreas caused by fibromatosis invasion of that organ as a part of FAP.     

Surgical treatment of familial adenomatous polyposis: Experience from a single institution in China

Aim: Surgical options for familiar adenomatous polyposis (FAP) have been standardized in developed countries but are still controversial in China. The aim of this study was to retrospectively evaluate the results of patients with FAP treated in a university hospital. Methods: In all 42 consecutive patients with FAP were operated on between May 1988 and June 2008. Median follow up was 7.2 years (2.2–20 years). Of these 33 patients were treated by proctocolectomy and ileal pouch anal anastomosis. A total colectomy with ileorectal anastomosis was undertaken in six and a proctocolectomy with ileostomy in three patients who had invasive rectal cancer. Results: Postoperative morbidity was insignificant. There were five wound infections, one intestinal obstruction, one anastomotic leakage, one anastomotic stenosis and one refractory pouchitis. One patient died from stroke. Five died from FAP‐related disorders, namely, abdominal desmoids, liver metastases and advanced rectal cancer. Desmoid tumor occurred in five patients. Periampullary adenoma and carcinoma developed in four patients. In those with pouch procedure the 24‐h bowel movement was 7.14 ± 1.28 (range 5–11) and their 10‐year overall survival was 87.5%. Conclusion: A proctocolectomy with ileal pouch anal anastomosis maybe the best choice for FAP patients in China. Surgical expertise, good teamwork and careful long‐term follow up are mandatory.     

Brain tumors in individuals with familial adenomatous polyposis: a cancer registry experience and pooled case report analysis

BACKGROUND: Most individuals with Familial Adenomatous Polyposis (FAP) harbor mutations in the APC gene on chromosome 5q21. They are at an increased risk of brain tumors, including cerebellar medulloblastoma, when compared with the general population (Brain Tumor Polyposis-BTP Type 2). Genotype-phenotype correlations between APC gene mutations and central nervous system (CNS) tumors have, thus far not been successful. Herein the authors have pooled their registry experience in BTP type 2 with the published reports. METHODS: The authors analyzed their established hereditary CRC Registry for brain tumors in FAP pedigrees (56 families, 213 individuals), pooled their patients with BTP and known APC mutations with those reported thus far elsewhere, and compared the resulting mutation distribution of FAP-BTP with the mutation distribution for APC mutations in the US. RESULTS: Twenty-eight patients from 24 families were accrued, the most common brain tumor in BTP was medulloblastoma (60%) predominantly in females (12:5) under the age of 20 (mean age 14.7 SD 9.2). Other histologic subtypes included astrocytoma and ependymoma. Analysis of the pooled APC mutation data by Chi-square test of association shows an odds ratio of 3.7 (P < .005) for all brain tumor subtypes and 13.1 (P < .001) for medulloblastoma in patients harboring segment 2 APC mutation (codons 679-1224) compared to nonsegment 2 mutation. CONCLUSIONS: In patients with FAP and identifiable APC gene mutation, CNS tumors, especially medulloblastoma which developed in most cases during childhood, are more common in females with FAP and APC gene mutation in codons 686-1217. Further studies are necessary to determine if this observation and the natural history of medulloblastoma in children justifies novel, aggressive, targeted screening of at-risk individuals.     

Total gastrectomy with isoperistaltic jejunal interposition flap for symptomatic management of gastric polyposis from familial adenomatous polyposis

Patients with familial adenomatous polyposis (FAP) oftentimes have extracolonic polyps. The patient discussed in this case report had innumerable gastric polyps which were significantly affecting his ability to tolerate oral intake and his overall nutrition. Medical management was not sufficiently controlling his symptoms; therefore we proceeded with surgical intervention. We discuss the use of a total gastrectomy with an Isoperistaltic jejunal interposition flap for the symptomatic management of gastric polyposis. We describe the technique used and benefits to this specific procedure when it comes to long term outcome, complications, and monitoring.     

家族性腺瘤性息肉病18例报道

探讨家族性腺瘤性息肉病的临床特点和治疗问题。方法 对1984-2002年收治的18例病人进行回顾性分析。结果 有家族史者9例,癌变8例。手术方式:全结肠直肠切除8例,其中回肠造口2例,回肠储袋肛管吻合6例;结肠次全切除6例,其中回肠直肠吻合5例,升结肠肛管吻合1例;结肠部分切除2例;Miles术1例,结肠会阴造口1例。结论 认识该病的临床特点,根据息肉的分布特点和有无癌变等选择不同的手术方式,首选结直肠全切回肠储袋肛管吻合术。     

Desmoid tumour in familial adenomatous polyposis. A review of literature

Desmoid tumours (DT) are rare benign tumours that do not metastasise, but tend to invade locally. DT are frequently seen in patients with familial adenomatous polyposis (FAP), and diagnosis and treatment are often difficult. Surgical trauma, genetic predisposition and hormonal factors are considered to be correlated with the development and growth of DT. In patients with FAP, 50% of the tumours are localised intra-abdominally, and 85–100% of these are mesenteric. DT frequently present as non-tender, slowly growing masses. The symptoms are abdominal pain, vomiting, diarrhoea or haematochezia. Mesenteric DT can cause small bowel obstruction or ischaemia, hydronephrosis or form fistulas. Diagnosis is obtained through biopsy and the extension is determined by a CT-scan. Surgical excision is recommended in patients with DT in the abdominal wall. First line treatment of mesenteric DT is a NSAID in combination with tamoxifen. Surgery may be considered in case of a small and well-defined DT with no signs of invasion of vital structures, and in cases of imminent bowel ischaemia or obstruction. The prognosis in mesenteric DT is serious, and improvement of the therapeutic strategy awaits current international studies.     

Using genotype to assist clinical surveillance: a retrospective study of Chinese familial adenomatous polyposis patients

Without treatment, familial adenomatous polyposis (FAP) patients will inevitably develop colorectal cancer (CRC) during lifetime. Yet, surgical trauma is a high risk of desmoid tumor (DT), one of the main causes of death in FAP patients. So far, the timing for colectomy is primarily based on the clinician’s experience and the patient’s preference; most patients undergo surgery at mid-20’s. In this study, we analyzed the germline mutation distribution in 35 FAP patients from different families, 16 of them diagnosed with DTs. We also investigated the association between the molecular alterations and the clinicopathological features. Capture-based targeted sequencing using a panel of 520 genes was performed on tumor tissue and paired normal mucosa or white blood cells from 18 FAP probands who were initially diagnosed with CRC. Of all 35 FAP patients, 30 (85.7%) of them harbored germline APC mutations scattered from codon 161 to 1578. The mutations in the 16 DT patients scattered from codon 457 to 1578. All three patients with the mutation at the 3’ of 1444 codon were diagnosed with DT. The percentage of high-risk DT (stage III or IV) harboring mutations at the 5’ of 1062 or 1062-1578 was 14.3% and 77.8%, respectively, and all three patients with 3’ of 1399 codon mutation had high risk. In addition, by using public database, we compared 140 FAP patients with DT to all 1880 FAP patients on the Leiden Open Variation Database and found that the odd ratio of DT in codon 159 to 495 was 0.34, while in codon 1310 to 2011 was 2.36. Compared to sporadic CRCs, the somatic spectrum of FAP CRCs was similar to the early onset CRCs, with higher TP53 (94.1%) and lower somatic APC mutations (65.7%), but the KRAS mutation rate was the highest (58.5%). One of the 18 FAP CRCs was identified as microsatellite instability-high (MSI-H), with tumor mutation burden (TMB) of 115.65 mut/Mb. Given that no TP53 mutations were detected in the low- and high-grade adenomas, ctDNA TP53 sequencing might be used for the close monitoring before FAP colectomy. In conclusion, except mutations at the 5’ end of APC (5’ to 495), all FAP patients need to consider the risk of DT after colectomy. The chance of life-threating DTs was higher in patients with 3’ 1062 codon mutation and peaked in patients with 3’ 1399 codon mutation. Scheduled monitoring of TP53 ctDNA is proposed to be a novel tool for optimizing the operation time.     

三器械联合应用于IPAA治疗家族性腺瘤性息肉病的体会

目的 总结家族性腺瘤性息肉病(FAP)的诊断和二器械联合IPAA外科治疗经验。方法 回顾分析19例FAP的临床资料及IPAA手术治疗效果。结果 所有患者预后良好，无明显并发症的发生，术后大便控制能力良好，术后癌变率与传统手术无差异，手术时间缩短、手术难度降低。结论 三器械联合IPAA手术是治疗FAP的最佳方法，易于推广。     

Attenuated familial adenomatous polyposis (AFAP): a review of the literature

Over the last decade, a subset of familial adenomatous polyposis(FAP) patients with a milder course of disease termed attenuated familial adenomatous polyposis (AFAP) has been described. AFAP is not well-defined as a disease entity – the reports on AFAP are largely casuistic or only deal with a few kindreds – and the diagnostic criteria and methods of investigation differ markedly. The true incidence and frequency of AFAP is not known. The mutations in APC associated with AFAP have mainly been detected in three parts of the gene: in the 5′ end (the first five exons), in exon 9 and in the distal 3′ end. The main features of AFAP are 100 or less colorectal adenomas with a tendency to rectal sparing, a delay in onset of adenomatosis and bowel symptoms of 20–25 years, a delay in onset of colorectal cancer (CRC) of 10–20 years and death from CRC of 15–20 years, and although the lifetime penetrance of CRC appears to be high, CRC does not seem to develop in nearly all affected patients. A more limited expression of the extracolonic features is seen, but gastric and duodenal adenomas are frequently encountered. Colonoscopy is preferred to sigmoidoscopy, should begin at the age of 20–25 years and no upper age limit of stopping surveillance is justified. Regular esophago-gastro-duodenoscopy (EGD) is recommended. Until further research has provided us with a more substantiated knowledge about AFAP changes in current surveillance and treatment are not recommended. Prophylactic colectomy with ileorectal anastomosis (IRA) is recommended in most patients.     

Profuse familial adenomatous polyposis with an Adenomatous Polyposis Coli exon 3 mutation

The attenuated form of familial adenomatous polyposis coli (AAPC) is associated with mutations in the adenomatous polyposis coli (APC) gene which cluster in the 5 region of the gene. It has been proposed that a 'genotype–phenotype boundary' exists at codons 159–163, and mutations that are 5 of this boundary will produce AAPC. Herein we document a three-generation family with an exon 3 mutation well to the 5 side of the proposed boundary, in which two affected individuals have had, in their 40s, a profuse form of familial adenomatous polyposis coli. We conclude that the codon 159–163 'boundary' is indicative rather than definitive. These two patients also had postoperative intra-abdominal adhesions, severely so in one.     

Possible involvement of hyperlipidemia in increasing risk of colorectal tumor development in human familial adenomatous polyposis

BACKGROUND: Familial adenomatous polyposis (FAP) results from germline adenomatous polyposis coli (APC) gene mutations and many affected patients die from colorectal cancers which arise from colorectal polyps. We previously reported that two strains of Apc gene-deficient mice developing multiple intestinal polyps exhibit a hyperlipidemic state. The triglyceride (TG) levels were approximately 10-fold higher than the levels observed in wild-type mice. METHODS: To examine whether a positive relationship might exist between hyperlipidemia and colorectal tumor development in FAP patients, as with Apc gene-deficient mice, a pilot experiment was performed using readily available clinical data such as ages, serum lipid levels, number of colorectal polyps and cancer development in 28 FAP patients from the National Cancer Center Hospital, Japan. RESULTS: The overall prevalence of hyperlipidemia in FAP cases was 58%. Average TG levels in the 40-60 year age groups of FAP patients were > or =150 mg/dl (the defined threshold level of hyperlipidemia). Moreover, there was a tendency for higher serum TG levels in patients who developed colorectal cancer, as compared with those without colorectal cancer. CONCLUSIONS: These results show that a hyperlipidemic state occurs in FAP patients. Although it is weaker than that in Apc gene-deficient mice, it may be linked to colon tumor development. These data warrant further studies for wider populations of FAP patients.     

Balance between endoscopic and genetic information in the choice of ileorectal anastomosis for familial adenomatous polyposis

BACKGROUND AND OBJECTIVES: The number of rectal polyps and the site of mutations in the APC (Adenomatous polyposis coli) gene have been used to guide the surgical management in patients with familial adenomatous polyposis (FAP). The aim of this study is to assess the utility of the APC mutation screening compared to the degree of the rectal polyposis in surgical decision making. METHODS: The post-surgical courses of 25 patients submitted to subtotal colectomy with ileorectal anastomosis (IRA) were reviewed. Preservation of the rectum was prospectively decided on the basis of well-defined endoscopic criteria. The number of rectal polyps was assessed preoperatively and every 6-12 months. APC gene was screened for mutations by heteroduplex analysis, single strand conformation polymorphism, in vitro synthesized protein (IVSP), and DNA sequencing. Patients negative for APC mutations were tested for MYH mutations. RESULTS: On the basis of preoperative polyp rectal count we categorized patients as follows: Group I, 5 or fewer adenomas; Group II, 6-9 adenomas; Group III, 10 or more adenomas. After a follow-up ranging from 12 to 225 months we have observed a significant difference of recurrent rectal adenomas between Groups I-II versus III. No difference was detected among patients of Group I and II. The mean number of adenomas/year/patient was 0.67, 1.62, and 9.29 for Group I, II, and III, respectively. Carpeting polyposis of the rectal stump developed in three patients with APC mutation at codon 1309 and two of them needed later proctectomy. Diffuse rectal polyposis was observed in one patient with mutation at exon 9 who had 10 small polyps at time of surgery. Mutation at the 5'-end of APC (codons 144-232), mutation of MYH and unknown APC or MYH mutation were correlated with a low number of polyps both at presentation and follow-up. No IRA patients developed rectal cancer. CONCLUSIONS: In our experience fewer than 10 rectal polyps at presentation can predict a favorable outcome after IRA. Identification of specific germ-line APC or MYH mutation can address the choice of surgical treatment.     

FAP with concurrent duodenal adenomatous polyposis and carcinoid tumor

We report a patient with familial adenomatous polyposis (FAP) who developed duodenal adenomatosis with high-grade dysplasia and a periampullary carcinoid tumor several years after total colectomy. Only two prior case reports exist revealing carcinoid tumors in association with FAP. No genetic basis exists explaining the link between FAP and carcinoid tumors. However, the presence of two rare entities in the same patient might suggest an association and further research may be indicated.     

Management strategies in Lynch syndrome and familial adenomatous polyposis: a national healthcare survey in Japan

Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are major sources of hereditary colorectal cancer (CRC) and are associated with other malignancies. There is some heterogeneity in management strategies in Japan. We undertook a survey of management of hereditary CRC in hospitals that are members of the Japan Society of Colorectal Cancer Research. One hundred and ninety departments responded, of which 127 were from designated cancer care hospitals (DCCHs) according to the Japanese government. There were 25 488 operations for CRC in these departments in 2015. The DCCHs performed better with regard to usage of Japan Society of Colorectal Cancer Research guidelines, referring new CRC patients for LS screening, and having in‐house genetic counselors and knowledge of treatment for LS. There were 174 patients diagnosed with LS and 602 undergoing follow‐up in 2011–2015, which is fewer than the number expected from CRC operations in 2015. These numbers were not affected by whether the institution was a DCCH. Universal screening for LS was carried out in 8% of the departments. In contrast, 541 patients were diagnosed with FAP and 273 received preventive proctocolectomy/colectomy in 2011–2015. The DCCH departments undertook more surgery than non‐DCCH departments, although most of the management, including surgical procedures and use of non‐steroidal anti‐inflammatory drugs, was similar. Management of desmoid tumor in the abdominal cavity differed according to the number of patients treated. In conclusion, there was heterogeneity in management of LS but not FAP. Most patients with LS may be overlooked and universal screening for LS is not common in Japan.     

家族性多发性息肉症腺瘤的早期分子生物学变化--单个腺体微解剖分析

目的：研究来自１０个家族性多发性肠息肉症（ＦＡＰ）患者１４个腺瘤的早期分子病理学变化。方法：将腱生蛋白（ｔｅｎａｓｃｉｎ,ＴＮ）阳必单个腺体经微解剖分离得ＤＮＡ,分析肿瘤相关基因位点的变化。结果：２例患者的ＴＮ阳性腺体分别出现５ｐｌ２及１８ｐ１２位点的杂合性技失（ＬＯＨ）。５ｐ１２位点的ＬＯＨ在所有ＴＮ阳性腺体分别出现５ｑ１２及１８ｑ１２位点的杂合性丢失（ＬＯＨ）。５ｑ１２位点的ＬＯＨ在所有ＴＮ阳     

Genotype and phenotype of patients with both familial adenomatous polyposis and thyroid carcinoma

The incidence of thyroid carcinoma in familial adenomatous polyposis (FAP) is thought to be 1%–2%, with the majority of cases being female. We have investigated the phenotype and genotype of 16 patients with FAP associated thyroid carcinoma. Among 1194 FAP patients studied in two high risk registries in North America (Familial Gastrointestinal Cancer Registry, Toronto and University California, San Francisco), 16 (1.3%) unrelated patients with FAP associated thyroid cancers were identified. Adenomatous polyposis coli (APC) gene testing was performed in 14 of the 16 cases. The average age of diagnosis for FAP and thyroid carcinoma was 29 years (range 17–52 years) and 33 years (range 17–55 years), respectively. All FAP patients except 1 had more than 100 colonic adenomas. Extracolonic manifestations, beside thyroid cancer, were presented in 81% (n = 13) of the patients, including gastric and duodenal polyps, desmoid tumor, osteoma, epidermoid cyst, sebaceous cyst and lipoma. Colorectal cancer was diagnosed in 38% (n = 6) of the patients. The pathology of the FAP associated thyroid cancer was predominantly papillary carcinoma. Germline mutations were identified in 12 of 14 patients tested. Mutations proximal to the mutation cluster region (1286–1513) were detected in 9 cases. Thyroid cancer in our FAP population was rare, predominantly in females and showed papillary carcinoma histology. Additionally, thyroid cancer in our patients occurred in the setting of classic FAP phenotype. Germline mutations were located predominantly outside the APC mutation cluster region. This revised version was published online in August 2006 with corrections to the Cover Date.     

COX-2在直肠腺瘤性息肉与癌组织中的表达及意义

目的 :研究COX 2在直肠家族性腺瘤性息肉病 (familialadenomatouspolyposis,FAP)与癌组织中的表达及意义。方法 :用流式细胞仪 (FCM )分别检测 1 2例正常直肠粘膜组织、1 9例FAP、7例FAP癌变组织及 36例直肠癌组织的COX 2蛋白表达。结果 :1 2例正常直肠粘膜组织COX 2蛋白表达的平均FI值为 0 .67± 0 .2 8,均呈阴性表达 ;FAP 1 8(94.74% )例、FAP癌变组织 7(1 0 0 % )例及直肠癌组织 36 (1 0 0 % )例阳性表达 ,COX 2蛋白表达平均FI值分别为 1 .97± 0 .36、2 .0 2± 0 .2 4、2 .1 4± 0 .31 ,COX 2蛋白表达及阳性表达率与正常直肠粘膜组织差异均有显著性 (P <0 .0 1 ) ,而三者之间差异无显著性 (P >0 .0 5)。结论 :提示COX 2蛋白表达检测对预测腺瘤性息肉癌变可能性、进而用化学干预具有重要意义